Zirconiuni(IV) chloride as a new, highly efficient, and reusable catalyst for acetylation of phenols, thiols, amines, and alcohols under solvent-free conditions

Article abstract of DOI:10.1055/s-2004-815442

Zirconium(IV) chloride has been found to be a new, highly efficient, and reusable catalyst for acetylation of structurally diverse phenols, thiols, amines, and alcohols under solvent-free condtions. Acetylation of sterically hindered and electron deficient phenols is achieved in excellent yields with stoichiometric amounts of Ac₂O at room temperature. Acid-sensitive alcohols undergo acetylation with excellent chemoselectivity without competitive side reactions such as dehydration or rearrangement. The mild Lewis acid property of the catalyst enables the acetylation to be carried out with optically active substrates without any detrimental effect on the optical purity.

Full text of DOI:10.1055/s-2004-815442

LETTER
627
Zirconium(IV) Chloride as a New, Highly Efficient, and Reusable Catalyst
for Acetylation of Phenols, Thiols, Amines, and Alcohols under Solvent-Free
Conditions
Z
A
irconium(IV)
C
h
s
loride
–
A
i
Cataly
t
st
f
or
A
cetyla
K
tion . Chakraborti,* Rajesh Gulhane
National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, Punjab – 160062, INDIA
Fax +91 2214692; E-mail: akchakraborti@niper.ac.in
Received 18 December 2003
dehydration etc.) with acid-sensitive substrates necessitat-
Abstract : Zirconium(IV) chloride has been found to be a new,
highly efficient, and reusable catalyst for acetylation of structurally
diverse phenols, thiols, amines, and alcohols under solvent-free
ing the use of a large excess of Ac O and low temperature
2
(
e.g., –50 °C to –10 °C). We thought that the use of a met-
condtions. Acetylation of sterically hindered and electron deficient al salt derived from a protic acid weaker than TfOH
phenols is achieved in excellent yields with stoichiometric amounts should permit acetylation of acid-sensitive substrates
4+
of Ac O at room temperature. Acid-sensitive alcohols undergo without any potential side reaction. Since Zr has a high-
2
acetylation with excellent chemoselectivity without competitive
er charge-to-size value compared to most of the metal ions
side reactions such as dehydration or rearrangement. The mild
Lewis acid property of the catalyst enables the acetylation to be
carried out with optically active substrates without any detrimental
effect on the optical purity.
2
employed as acetylation catalysts (the Z /r values are 1.5,
2
–10
5
.4, 5.48, 5.56, 8.82, 11.39, 12.33 and 22.22 e m for
+
2+
2+
2+
3+
3+
3+
4+
Li , Co , Cu , Mg , Bi , In , Sc , and Zr , ions, re-
spectively) a zirconium derivative should be a better ac-
tivator of Ac O due to stronger coordination between Zr
1
2
Keywords: acetylation, zirconium compounds, catalysis, solvent-
free reactions
4+
2
and Ac O. Furthermore, the abundance of Zr(IV) com-
2
1
3
pounds in the earth’s crust makes them less costly and
easily available and zirconium compounds are regarded to
be of low toxicity.14 Thus, Zr(IV) compounds should be
ideal for catalytic applications as evidenced by their in-
creasing commercial use for this purpose.15 We disclose
Protection of phenols, thiols, alcohols, and amines is a fre-
quently encountered exercise in organic synthesis and is
1
usually achieved through acylation with anhydrides due
1
,2
to the ease of deprotection. The various catalysts devel-
herein our findings on the catalytic effects of ZrCl for
3
4
oped for acetylation include nucleophilic agents, Lewis
acetylation of phenols, thiols, amines, and alcohols.
4
5
6
acids such as metal halides, metal triflates, solid acids,
7
The reactions were carried out with one equiv of Ac O at
and metal perchlorates. Recently ionic liquids have been
employed for acetylation. The limitations of the existing
2
8
r.t. in 15–150 minutes (Table 1) in the presence of ZrCl
4
16
(
1 mol%). In general, the products obtained after usual
protocols are longer reaction times, stringent conditions,
use of halogenated solvents, use of hazardous materials
work up were clean (spectral analyses) and did not require
any further purification. The catalyst was recovered and
used for further acetylation without any significant loss of
catalytic activity. Excellent chemoselectivity was ob-
served – (i) no competitive Fries rearrangements17 were
observed for phenolic substrates, (ii) secondary and tertia-
ry alcohols did not experience any competitive dehydra-
tion (entries 27,29–32,38–40) and (iii) no rearrangement
took place for allylic and propargylic substrates (entries
[
5
e.g., DMAP is highly toxic (LD in the rat, intravenous:
50
9
6 mg/kg), Bu P is flammable (flash point: 37 °C) and air
3
1
0
sensitive, and perchloric acid and its salts are potentially
explosive], use of costly catalysts (e.g., the triflates), spe-
cial efforts required to prepare the catalyst (e.g., Bi(OTf)3,
Nafion-H, yttria-zirconia, HBF –SiO , and HClO –SiO ),
4
2
4
2
require the use of excess acylating agent, potential side re-
actions with acid-sensitive substrates, and in most of the
cases being applicable to alcohols only make the necessity
to develop a better acetylation method a high priority.
3
3,35,36,38–40). Acetylation of optically active sub-
strates (entries 18,31,32) resulted in excellent yields with-
out any detrimental effect on the optical purity.
Recently there has been an upsurge in the use of triflates
derived from rare earth, transition, and alkali metals as
The mildness of ZrCl in comparison to the metal triflates
4
5
is evidenced by the result obtained for alcoholic substrates
susceptible to undergo dehydration and/or rearrangement.
Thus, acetylation of 1-methyl-1-cyclohexanol requires 5
acylation catalysts. However, the high cost, commercial
nonavailability [for Bi(OTf) ], and susceptibility to mois-
3
ture do not make triflates good contenders for use in large
equivalents of Ac O at –20 °C or –10 °C for 5 hours dur-
scale synthesis. The large negative H value of –14.1 of
2
0
1
1
ing the Sc(OTf) or TMSOTf catalyzed reaction (9% of
TfOH makes the metal triflates very strong Lewis acids
and lead to potential side reactions (e.g., rearrangement,
3
5
the olefinic product was formed in the former case). The
use of LiOTf (30 mol%), requires 6 equivalents of Ac O
2
5
to afford comparable results in 30 hours. In comparison
SYNLETT 2004, No. 4, pp 0627–0630
0
9.
0
3.
2
0
0
4
to these, ZrCl catalyzed the reaction at room temperature
Advanced online publication: 29.01.2004
4
DOI: 10.1055/s-2004-815442; Art ID: D26903ST
within 0.75 hours with 1 equivalent of Ac O.
2
©
Georg Thieme Verlag Stuttgart · New York

6
28
A. K. Chakraborti, R. Gulhane
LETTER
Table 1 ZrCl Catalyzed Acetylation of Phenols, Thiols, Amines,
and Alcohols
Table 1 ZrCl Catalyzed Acetylation of Phenols, Thiols, Amines,
and Alcohols (continued)
4
4
a
a
Time (h) Yield (%)b
Entry Substrate
1
Time (h) Yield (%)b
Entry Substrate
OH
0.25
95
R1
R2
R
3
OH
1
2
3
2
2
5
6
R = R = H; R = Ph
0.25
0.75
0.75
0.5
90
90
95g
92
95
98g
90
OH
R4
R1
1
2
3
R = R = H; R = H CPh
2
R2
1
2
3
27
28
29
30
31
R = H; R = Me; R = Ph
R3
1
2
3
1
2
4
3
R = COPh; R = H; R = Ph 0.5
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
R = R = R = H; R = OMe
0.25
0.25
1.5
1
95
1
2
3
1
2
4
3
R = Et; R = H; R = Ph
0.75
0.75
0.5
R = OMe; R = R = H; R = Me
99
1
2
3
1
4
t
2
3
90c
R = Me; R ; R = (H C)
R = R = Bu; R = H; R = Me
2
5
1
4
t
2
3
86c
OH
R = R = Bu; R = H; R = OMe
1
3
4
2
93c
92
95
97
90
94
86d
R = R = R = Me; R = H
2
1
2
4
3
32
33
0.5
92
R = R = R = H; R = Br
0.5
0.5
0.5
0.5
0.25
1
1
2
4
3
R = R = R = H; R = COMe
OH
OH
1
2
4
3
100h
90c
R = R = R = H; R = CO Me
1
2
1
2
4
3
1
1
1
1
1
1
1
1
1
R = R = R = H; R = CN
3
3
4
5
0.25
1
2
4
3
R = R = R = H; R = NO
2
OH
1
2
3
4
R = NO ; R = R = R = H
2
50i,j,k
92l
HO
2
1
1
2
4
3
94e
R = R = R = H; R = OH
0.25
0.25
0.25
0.5
0.5
2
1
2
3
4
94e
36
OH
R = OH; R = R = R = H
2
1
3
4
93e
R = OH; R = R = R = H
R1
2
1
4
3
85e
R = OH; R = R = H; R = t-Bu
R2
HO
1
R3
1
2
3
4
80f
R = R = OH; R = R = H 0.5
2
3
3
3
7
8
R = R = R = H
0.5
1
100
100
100
90g
O
H
100
1
2
3
R = R = Me; R = H
Me
N
OEt
H
1
2
3
O
39
R = Et; R = Me; R = H
1
1
2
3
4
0
R ,R = (CH ) ; R = H
1.5
2
5
OH
(CH2)nSH
a
The substrate was treated with Ac O (1 equiv per OH, SH, or NH
2
group (except for entries 4–6 and 34–36) in the presence of ZrCl4
R
(
1 mol%) under neat conditions (except for entries 27,30,33, and 40)
1
2
2
2
9
0
1
2
R = H; n = 0
R = H; n = 1
1
1
1
1
95
90
98
97
at r.t.
b
Isolated yield of the corresponding acetylated product.
The reaction was carried out with 1.5 equiv of Ac O.
The reaction was carried out at 80 °C.
Isolated yield of the diacetate.
Isolated yield of the triacetate.
The reaction was carried out in MeCN.
The reaction was carried out in DCM.
GCMS yield with 2 equiv of Ac O.
The unreacted starting material remains unchanged.
The reaction was catalyzed by Bi(OTf) resulted in an intractable
c
d
e
f
2
R = Me; n = 0
R = OMe; n = 0
g
h
i
R2
NH2
2
j
R1
k
3
1
2
2
2
3
4
R = NO ; R = H
1
97
85
product mixture.
2
l
The reaction was carried out with 2 equiv of Ac O.
2
1
2
R = R = NO
0.5
2
Synlett 2004, No. 4, 627–630 © Thieme Stuttgart · New York

LETTER
Zirconium(IV) Chloride – A Catalyst for Acetylation
629
The Sc(OTf) catalyzed acetylation of 1-ethynyl-1-cyclo- References
3
hexanol necessitates the use of 3 equivalents of Ac O at
2
(
1) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999.
2) (a) Chakraborti, A. K.; Nayak, M. K.; Sharma, L. J. Org.
Chem. 2002, 67, 1776. (b) Chakraborti, A. K.; Nayak, M.
K.; Sharma, L. J. Org. Chem. 2002, 67, 2541.
–
20 °C and a 94%, 88%, and 62% yields of the ace-
tylated product could be obtained using 10 equivalents
of Ac O in MeCN/CH Cl within 2–4 h at r.t. in the pres-
(
2
2
2
5
ence of Bi(OTf) , Sc(OTf) , and TMSOTf, respectively.
3
3
(c) Chakraborti, A. K.; Sharma, L.; Sharma, U. Tetrahedron
The reaction catalyzed by ZrCl afforded 90% yields with
4
2001, 57, 9343. (d) Chakraborti, A. K.; Nayak, M. K.;
1
equivalent of Ac O at room temperature within 0.5
2
Sharma, L. J. Org. Chem. 1999, 64, 8027.
hours. Acetylation of linalool is catalyzed by Sc(OTf) us-
3
(3) (a) DMAP: Steglich, W.; Höfle, G. Angew. Chem., Int. Ed.
ing Ac O as solvent at –20 °C providing a 68% yield of
2
Engl. 1969, 8, 981. (b) Bu P: Vedejs, E.; Diver, S. T. J. Am.
3
the expected product along with 8% of the rearrangement
Chem. Soc. 1993, 115, 3358.
5
product in 2.5 hours. Treatment with 3 equivalent of
(4) (a) CoCl : Ahmad, S.; Iqbal, J. Tetrahedron Lett. 1986, 27,
2
Ac O at –25 °C for 5 hours in the presence of Cu(OTf)2
3791. (b) TaCl : Chandrasekhar, S.; Ramachander, T.;
5
Takhi, M. Tetrahedron Lett. 1998, 39, 3263. (c) InCl3:
Chakraborti, A. K.; Gulhane, R. Tetrahedron Lett. 2003, 44,
2
affords 83% yield of the acetylated products that contain
9
% of the rearranged product and the use of TMSOTf fails
6749.
5
to produce any expected product. Use of ZrCl resulted in
4
(5) (a) Sc(OTf) : Ishihara, K.; Kubota, M.; Kurihara, H.;
3
5
0% yield of the desired product with 2 equivalents of
Yamamoto, H. J. Org. Chem. 1996, 61, 4560.
Ac O in the absence of solvent in 2 hours at room temper-
2
(b) Sc(NTf ) : Ishihara, K.; Kubota, M.; Yamamoto, H.
2 3
ature without any concomitant formation of the rear-
ranged product. However, an intractable product mixture
was obtained when the reaction was carried out in the
Synlett 1996, 265. (c) TMSOTf: Procopiou, P. A.; Baugh, S.
P. D.; Flack, S. S.; Inglis, G. G. A. J. Org. Chem. 1998, 63,
2
342. (d) Bi(OTf) : Orita, A.; Tanahashi, C.; Kakuda, A.;
3
Otera, J. J. Org. Chem. 2001, 66, 8926. (e) Cu(OTf)2:
Chandra, K. L.; Sarvanan, P.; Singh, R. K.; Singh, V. K.
presence of Bi(OTf) under similar conditions. Acetyla-
3
tion of geraniol requires 10 equivalents of Ac O and
2
Tetrahedron 2002, 58, 1369. (f) Cu(OTf) : Chauhan, K. K.;
2
MeCN as co-solvent during the Sc(OTf) catalyzed reac-
3
Frost, C. G.; Love, I.; Waite, D. Synlett 1999, 1743.
5
tion to afford a 64% yield in 24 hours. The Bi(OTf) cat-
(g) Ce(OTf) : Dalpozzo, R.; De Nino, A.; Maiuolo, L.;
3
3
alyzed reaction affords a 81% yield in 3.5 hours under
Procopio, A.; Nardi, M.; Bartoli, G.; Romeo, R. Tetrahedron
Lett. 2003, 5621. (h) LiOTf: Karimi, B.; Maleki, J. J. Org.
Chem. 2003, 68, 4951.
neat conditions and 90% yield in 24 hours in MeCN with
5
1
0 equivalents of Ac O. Acetylation with 3 equivalents
2
(
6) (a) Clays: Li, A.-X.; Li, T.-S.; Ding, T.-H. Chem. Commun.
of Ac O at –25 °C provides a 90% yield in 7 hours in the
2
1997, 1389. (b) Zeolites: Ballini, R.; Bosica, G.; Carloni, S.;
5
presence of Cu(OTf) . The ZrCl catalyzed reaction with
2
4
Ciaralli, L.; Maggi, R.; Sartori, G. Tetrahedron Lett. 1998,
39, 6049. (c) Nafion-H: Kumareswaran, R.; Pachamuthu,
K.; Vankar, Y. D. Synlett 2000, 1652. (d) Yttria-zirconia:
Kumar, P.; Pandey, R. K.; Bodas, M. S.; Dongare, M. K.
Synlett 2001, 206. (e) HBF –SiO : Chakraborti, A. K.;
2
equivalents of Ac O afforded a 94% yield in MeCN for
2
2
hours and 92% yield under neat conditions in 1 hour.
The incompatibality of the metal triflates for acetylation
of acid-sensitive substrate is further exemplified by the re-
4
2
Gulhane, R. Tetrahedron Lett. 2003, 44, 3521. (f) HClO4–
action of 1-phenyl-1-propanol. Thus, the Ce(OTf) cata-
3
SiO : Chakraborti, A. K.; Gulhane, R. Chem. Commun.
2
lyzed acetylation using Ac O as solvent does not give any
2
2003, 1896.
acetylated product at room temperature and the desired
(
7) (a) LiClO : Nakae, Y.; Kusaki, I.; Sato, T. Synlett 2001,
4
5
product is obtained at –10 °C for 6 hours. In comparison
1584. (b) Chakraborti, A. K.; Sharma, L.; Gulhane, R.;
to these, the desired product was obtained in 95% yield at
Shivani Tetrahedron 2003, 59, 7661. (c) Bartoli, G.; Bosco,
M.; Dalpozzo, R.; Marcantoni, E.; Massaccesi, M.; Rinaldi,
S.; Sambri, L. Synlett 2003, 39. (d) BiO(ClO4)2:
Chakraborti, A. K.; Gulhane, R.; Shivani Synlett 2003,
1805.
room temperature with 1 equivalent of Ac O in 0.75 hours
2
during the ZrCl catalyzed reaction.
4
In conclusion, ZrCl is a new and highly efficient catalyst
4
for acetylation of phenols, thiols, amines, and alcohols.
The advantages include the low cost of the catalyst, oper-
ation at room temperature, high yields, and excellent
chemoselectivity. With the increasing tight legislation on
the release of waste and use of toxic substances as a mea-
(8) Forsyth, S. A.; MacFarlane, D. R.; Thomson, R. J.; von
Itzstein, M. Chem. Commun. 2002, 714.
(
9) Sweet, D. V. Registry of Toxic Effects of Chemical
Substances 1985-86; U. S. Govt. Printing Office:
Washington D.C., 1988, 3336, 4049.
(
(
10) Buckler, S. A. J. Am. Chem. Soc. 1962, 84, 3093.
11) Olah, G. A.; Prakash, G. K. S. Superacids; Wiley: New
York, 1985.
(12) Huheey, J. E. Inorganic Chemistry: Principles of structure
and Reactivity, 3rd ed.; Harper & Row: Singapore, 1990,
Chap. 7.
1
8
sure to control environmental pollution, the use of sto-
ichiometric amount of the acetylating agent, non-toxic
1
9
nature of ZrCl [LD in the rat, oral: 1688 mg/kg], and
4
50
solvent free condition employed in the present method
make it ‘environmentally friendly’ and suitable for indus-
trial applications.
(
13) Riley, J. P.; Chester, R. Introduction to Marine Chemistry;
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(
14) Farnworth, F.; Jones, S. L.; McAlpine, I. Speciality
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Synlett 2004, No. 4, 627–630 © Thieme Stuttgart · New York

6
30
A. K. Chakraborti, R. Gulhane
LETTER
(
16) Typical procedure for acetylation: 2-Hydroxy-
sample of 2-acetoxynaphthalene. The recovered catalyst was
naphthalene(1) (1.44 g, 10 mmol) was treated with Ac O
used for the acetylation of a fresh lot of 1 (1.44 g, 10 mmol)
2
(
0.96 mL, 10 mmol) under neat conditions at r.t. for 15 min
with Ac O (0.96 mL, 10 mmol) affording 2-
2
under magnetic stirring in the presence of ZrCl (23 mg, 0.1
acetoxynaphthalene (1.73 g, 93%).
4
mmol, 1 mol%). The reaction mixture was diluted with Et O
(17) Harrowven, D. C.; Dainty, R. F. Tetrahedron, Lett. 1996, 37,
7659.
2
(50 mL) and the supernatant solution decanted off to
separate the catalyst. The filtrate was washed successively
with 2% aqueous NaOH (15 mL), brine (15 mL), dried
(18) Garrett, R. L. In Designing Safer Chemicals, American
Chemical Society Symposium Series 640; Garrett, R. L.; De
Vito, S. C., Eds.; American Chemical Society: Washington
DC, 1996, Chap. 1.
(
MgSO ) and concentrated to afford the product (1.77 g,
4
9
5%), which was in full agreement with the mp and spectral
1
13
data (IR, H and C NMR, and EIMS) of an authentic
(19) Emsley, J. The Elements, 3rd Ed.; Clarendon: Oxford, 1998.
Synlett 2004, No. 4, 627–630 © Thieme Stuttgart · New York